Methotrexate treatment affects effector but not regulatory T cells in juvenile idiopathic arthritis

Rheumatology (United Kingdom)

Volumn 54, Issue 9, 2015, Pages 1724-1734

  Ćalasan, Maja Bulatović ^a   Vastert, Sebastiaan J ^a   Scholman, Rianne C ^a   Verweij, Frederik ^a   Klein, Mark ^a   Wulffraat, Nico M ^a   Prakken, Berent J ^a   van Wijk, Femke ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

Cytokines; Effector T cells; Juvenile idiopathic arthritis; Methotrexate; Regulatory T cells; Suppression assays

Indexed keywords

CD3 ANTIGEN; GAMMA INTERFERON; INTERLEUKIN 13; INTERLEUKIN 17; METHOTREXATE; TUMOR NECROSIS FACTOR ALPHA;

ADOLESCENT; ADULT; ARTICLE; BLOOD SAMPLING; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL FUNCTION; CHILD; CYTOKINE PRODUCTION; EFFECTOR CELL; EFFECTOR T CELL; FEMALE; FLOW CYTOMETRY; HUMAN; HUMAN CELL; INVESTIGATIVE PROCEDURES; JUVENILE RHEUMATOID ARTHRITIS; LOW DRUG DOSE; LYMPHOCYTE PROLIFERATION; MAJOR CLINICAL STUDY; MALE; PHENOTYPE; PRIORITY JOURNAL; QUALITATIVE RESEARCH; QUANTITATIVE STUDY; REGULATORY T LYMPHOCYTE; TREATMENT DURATION; TREATMENT RESPONSE;

EID: 84983177964     PISSN: 14620324     EISSN: 14620332     Source Type: Journal    
DOI: 10.1093/rheumatology/kev101     Document Type: Article

References (47)

1. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011;377:2138-49.
2. Wehrens EJ, Prakken BJ, van Wijk F. T cells out of control-impaired immune regulation in the inflamed joint. Nat Rev Rheumatol 2013;9:34-42.
3. Mijnheer G, Prakken BJ, van Wijk F. The effect of autoimmune arthritis treatment strategies on regulatory T-cell dynamics. Curr Opin Rheumatol 2013;25:260-7.
4. bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 2004;172: 6435-43.
5. Haufe S, Haug M, Schepp C et al. Impaired suppression of synovial fluid CD4 + CD25-T cells from patients with juvenile idiopathic arthritis by CD4 + CD25 + Treg cells. Arthritis Rheum 2011;63:3153-62.
6. Wehrens EJ, Mijnheer G, Duurland CL et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood 2011;118:3538-48.
7. Foell D, Wulffraat N, Wedderburn LR et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA 2010;303: 1266-73.
8. Giannini EH, Brewer EJ, Kuzmina N et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and the Cooperative Children's Study Group. N Engl J Med 1992;326:1043-9.
9. Ruperto N, Murray KJ, Gerloni V et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum 2004;50:2191-201.
10. Woo P, Southwood TR, Prieur AM et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 2000;43:1849-57.
11. Beukelman T, Patkar NM, Saag KG et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res 2011;63: 465-82.
12. Chan ES, Cronstein BN. Methotrexate-how does it really work? Nat Rev Rheumatol 2010;6:175-8.
13. Montesinos MC, Takedachi M, Thompson LF et al. The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5'-nucleotidase: findings in a study of ecto-50-nucleotidase gene-deficient mice. Arthritis Rheum 2007;56:1440-5.
14. Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 1993;92: 2675-82.
15. Montesinos MC, Desai A, Delano D et al. Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum 2003;48:240-7.
16. Montesinos MC, Yap JS, Desai A et al. Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis. Arthritis Rheum 2000;43: 656-63.
17. Kobie JJ, Shah PR, Yang L et al. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol 2006;177: 6780-6.
18. Borsellino G, Kleinewietfeld M, Di MD et al. Expression of ectonucleotidase CD39 by Foxp3 + Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007;110:1225-32.
19. Deaglio S, Dwyer KM, Gao W et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204: 1257-65.
20. + regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol 2012;3: 190.
21. Genestier L, Paillot R, Fournel S et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998;102: 322-8.
22. Spurlock CF III, Tossberg JT, Fuchs HA, Olsen NJ, Aune TM. Methotrexate increases expression of cell cycle checkpoint genes via JNK activation. Arthritis Rheum 2012;64:1780-9.
23. Spurlock CF III, Aune ZT, Tossberg JT et al. Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. Arthritis Rheum 2011;63:2606-16.
24. Assaraf YG. Molecular basis of antifolate resistance. Cancer Metastasis Rev 2007;26:153-81.
25. Bulatovic Calasan M, Thurlings RM, Wulffraat NM, Prakken BJ. Translational medicine from bedside to bench and back again: methotrexate revisited. Int J Clin Rheumatol 2013;8:291-306.
26. Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 2006;54: 3095-103.
27. Dervieux T, Zablocki R, Kremer J. Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology 2010;49:2337-45.
28. Bulatovic Calasan M, den Boer E, de Rotte MC et al. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in juvenile idiopathic arthritis patients. Ann Rheum Dis 2015;74: 402-7.
29. Petty RE, Southwood TR, Manners P et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390-2.
30. Ruperto N, Ravelli A, Falcini F et al. Performance of the preliminary definition of improvement in juvenile chronic arthritis patients treated with methotrexate. Italian Pediatric Rheumatology Study Group. Ann Rheum Dis 1998;57:38-41.
31. de Jager W, Hoppenreijs EP, Wulffraat NM et al. Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann Rheum Dis 2007;66:589-98.
32. Ehrenstein MR, Evans JG, Singh A et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med 2004;200: 277-85.
33. McGovern JL, Nguyen DX, Notley CA et al. Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum 2012;64: 3129-38.
34. Wing K, Onishi Y, Prieto-Martin P et al. CTLA-4 control over Foxp3 + regulatory T cell function. Science 2008;322: 271-5.
35. Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci USA 2008;105:19396-401.
36. + immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16:311-23.
37. + regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135-42.
38. Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004;50:1370-82.
39. Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005;57: 163-72.
40. Evans HG, Suddason T, Jackson I, Taams LS, Lord GM. Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptoractivated monocytes. Proc Natl Acad Sci USA 2007;104: 17034-9.
41. Wehrens EJ, Vastert SJ, Mijnheer G et al. Anti-tumor necrosis factor α targets protein kinase B/c-Akt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis. Arthritis Rheum 2013;65:3279-84.
42. low regulatory T cells. Arthritis Rheum 2013;65:627-38.
43. Pesenacker AM, Bending D, Ursu S et al. CD161 defines the subset of FoxP3 + T cells capable of producing proinflammatory cytokines. Blood 2013;121:2647-58.
44. Lina C, Conghua W, Nan L, Ping Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol 2011;31:596-605.
45. Berg L, Ronnelid J, Klareskog L, Bucht A. Down-regulation of the T cell receptor CD3ζ chain in rheumatoid arthritis (RA) and its influence on T cell responsiveness. Clin Exp Immunol 2000;120:174-82.
46. dim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues. Blood 2007;109:4328-35.
47. Klein A, Kaul I, Foeldvari I et al. Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: an observational study with patients from the German Methotrexate Registry. Arthritis Care Res 2012;64:1349-56.